Fragile X syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Fragile X syndrome is the leading inherited cause of intellectual disorder and autism spectrum disorder with severe behavioral abnormalities . It is an X linked disorder, affecting both males and females. It is a genetic disease caused by CGG trinucleotide expansion (>200 CGG repeats).

Fragile X syndrome was described first by Martin and Bell in 1943.

There is no established system for the classification of Fragile X syndrome.

Fragile x syndrome has an x-linked dominant inheritance. It is caused by an expansion of CGG trinucleotide repeat within FMR1 gene on X chromosome. Due to high number of CGG repeats (>200), this leads to methylation of part of gene on X chromosome that codes for Fragile X Mental retardation protein (FMRP), which is required for proper development of connections between neurons.

Fragile x Syndrome is a genetic disease which is caused by mutation in the Fragile x Mental Retardation 1(FMR1) gene in X chromosome. Generally, these mutation (>200 repeats of CGG) occurs at in the 5′ untranslated region of FMR1. In around 2% of cases, Fragile X syndrome can occur as a result of point mutation in FMR1 gene.

Fragile X syndrome must be differentiated from Down’s Syndrome, Autism Spectrum Disorder, Attention deficit hyperactivity disorder (ADHD), Fragile XE syndrome (FRAXE), Klinefelter syndrome and Prader-Willi syndrome (PWS).

The prevalence of Fragile X syndrome is approximately 1 in 5000 men and 1 in 4000-6000 women worldwide, determined by molecular assays. Fragile X Syndrome has been diagnosed in approximately 3 percent of boys with significant neurodevelopmental disorders.

There are no established risk factors for Fragile X syndrome. However, the child with family history of Fragile x Syndrome, autism disorder of unknown cause, developmental delay, adult onset ataxia/tremor or any intellectual disabilities are at greater risk of developing the disorder.

Genetic counseling and prenatal screening is recommended when one of the parents is shown to be a carrier of fragile X. Prenatal testing can be done by amniocentesis at 16-20 weeks or by chorionic villus sampling (CVS) at 10-13 weeks to determine if a fetus has inherited the fragile X gene

The outcome depends on the extent of mental retardation. Life expectancy is normal.

The diagnosis of fragile X syndrome can be confirmed by molecular testing in the form of Triplet-primed PCR( Polymerase Chain Reactions) which shows the extent of expansion of CGG repeats.

Common symptoms of Fragile X syndrome include low IQ with learning difficulties (intellectual disabilities). Behavioral abnormalities includes stereotypic movements (e.g., hand-flapping) hyperactivity, inattention, poor social interaction, limited eye contact and poor memory. Child with Fragile X syndrome often presents with developmental delay (including delayed attainment of motor and language milestones)

Common physical examination findings of Fragile X syndrome include large and protruding ears, elongated face, macroorchidism (large testicles in men after puberty), flat foot, high arched palate, hyperflexible finger joints and low muscle tone.

There are no diagnostic laboratory findings associated with Fragile X syndrome.

There are no specific ECG findings associated with Fragile X syndrome.

There are no x-ray findings associated with Fragile X syndrome.

There are no CT scan findings associated with Fragile X Syndrome.

There are no specific MRI findings associated with Fragile X syndrome. However, some patient with Fragile X syndrome showed hyperintensities of the middle cerebellar peduncles.

There are no other diagnostic studies associated with Fragile X syndrome.

There is no specific treatment for Fragile X syndrome. There are some medication under trial such as fenobam (mGLUR5 antagonist) and Lithium (mGLUR5 signaling inhibitor).

Surgical intervention is not recommended for the management of Fragile X syndrome.

There are no established measures for the primary prevention of Fragile X syndrome.

There are no established measures for the secondary prevention of Fragile X syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

James Purdon Martin and Julia Bell first described fragile X syndrome in 1943. The association between fragile site in X chromosome and Fragile X syndrome was made in the year 1969.

Fragile X syndrome was described first by Martin and Bell, British geneticists, in 1943 while doing family case report with mental retardation. The disease was initially called as Martin Bell Syndrome after their discoveries. Later, a portion of X chromosome was found to be involved in all the patient with the disease, and the name was changed to Fragile X syndrome.

Martin JP, Bell J. A pedigree of mental defect showing sex- linkage. J Neurol Psychiatry. 1943; 6(3-4): 154–7

There is no established system for the classification of Fragile X syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

It is thought that Fragile X syndrome is caused by mutation in a gene, specifically FMR1 gene present on X chromosome. The CGG triplet repetition leads to hypermethylation of the gene, which ultimately leads to silencing of the FMR1 gene. The FMR1 gene codes for protein responsible for brain development. Due to this defect, the normal neuron development is affected.

Fragile x syndrome has an x-linked dominant inheritance. It is caused by an expansion of CGG trinucleotide repeat within 5′ UTR in FMR1 gene on X chromosome. Due to high number of CGG repeats (>200), this leads to methylation of part of gene on X chromosome that codes for Fragile X Mental retardation protein (FMRP), which is required for proper development of connections between neurons.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Fragile X syndrome is caused by a change to a FMR1 gene on the X-chromosome. This gene responsible for brain development and to function normally. If this gene is altered in any way, it cannot produce its FMR1 protein, which can result in Fragile X syndrome.

Fragile x Syndrome is a genetic disease which is caused by mutation in the Fragile x Mental Retardation 1(FMR1) gene in X chromosome. Generally, these mutation (>200 repeats of CGG) occurs at in the 5′ untranslated region of FMR1. In around 2% of cases, Fragile X syndrome can occur as a result of point mutation in FMR1 gene.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Fragile X syndrome must be differentiated from other diseases that cause mental retardation, change in stature, and increase in testicular size, such as sotos syndrome, Prader-willi syndrome and klinefelter syndrome.

Fragile X syndrome must be differentiated from Sotos syndrome, Prader-willi syndrome, Lujan syndrome, Learning difficulties, Autism spectrum disorder and Klinefelter syndrome, which are the common causes of intellectual disabilities.

• Sotos syndrome: Presents with intellectual disabilities, elongated face and tall stature.
• Prader-willi syndrome: Presents with intellectual disabilities, poor tone, distinctive facial features (almond shaped eye with narrowing of head at temples) and under developed genitals.
• Klinefelter: Presents with mild intellectual disabilities, tall stature and under-developed genitals.
• Lujan Syndrome: Presents with intellectual disabilities, tall/thin body, large head, behavioral abnormalities and hypotonia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The prevalence of female carrier status has been estimated to be as high as 1 in 130-250 population; the prevalence of male carrier status is estimated to be 1 in 250-800 population. However, disease manifestations are seen in lesser number of people.

The prevalence of Fragile X syndrome is approximately 1 in 5000 men and 1 in 4000-6000 women worldwide, determined by molecular assays. Fragile X Syndrome has been diagnosed in approximately 3 percent of boys with significant neurodevelopmental disorders.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

The most potent risk factor in the development of Fragile X syndrome is presence of Fragile X syndrome in any of family members. Other risk factors include family history of developmental delays, autism or intellectual deficit of unknown origin and infertility in the family.

Common risk factors in the development of Fragile X syndrome include family history of Fragile X syndrome, mental retardation or autism of unknown origin and developmental delays in the family members. Family history of infertility associated with elevated FSH levels or premature ovarian family have shown some linkage with Fragile X syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Routine screening for Fragile X syndrome is not recommended. Prenatal or preconceptional screening is only recommended among high risk individuals such as family members with history of mental retardation, movement disorders or Fragile X syndrome.

There is insufficient evidence to recommend routine screening for Fragile X syndrome. The gold standard test to look for CGG expansion is Polymerase chain reaction (PCR) followed by Southern blot test to refine expanded size and methylation status. For prenatal screening, samples are obtained from chorionic villus samples (CVS) at 11-13 weeks or amniocytes by amniocentesis at >15 weeks period of gestation.

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If left untreated, patients face more difficulties with learning activities and often leads to cognitive impairment. Common complications of Fragile X Syndrome include ear infections, vision problems that include strabismus, hyperopia, and astigmatism. Some cases have been reported having seizures. Life expectancy is normal.

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